The long-range goals of this 5-year proposal are to understand, in the CNS of genetically vulnerable subjects, the complex neuronal alterations that occur as a result of alcohol exposure, which promote high alcohol drinking behavior and relapse. The overall hypothesis is that, in individuals with a genetic predis-position for high alcohol drinking behavior, certain CNS neuronal circuits are susceptible to alterations by alcohol and, as a result, high alcohol drinking is initiated and maintained, and alcohol relapse drinking is promoted. The goals of the present proposal are to determine the long-term changes in gene and protein expression produced by voluntary alcohol drinking that may be associated with high alcohol drinking and relapse. Inbred adult male alcohol preferring (iP), high-alcohol-drinking (iliAD), alcohol-non-preferring (iNP) and low-alcohol-drinking (iLAD) rats will be used for these studies. The microchip expression array will be used to examine changes in gene expression, and 2-dimensional gel electrophoresis procedures will be used to examine changes in protein expression. The first 2 specific aims will compare innate differences between iP and iNP rats and between replicate iliAD and iLAD rats, and determine the effects of voluntary alcohol drinking by iP and iliAD rats on changes in gene and protein expression in the nucleus accumbens, prefrontal cortex and posterior hippocampus. The second 2 specific aims will examine the effects of operant oral alcohol self-administration, extinction training and reinstatement on gene and protein expression in these limbic regions of the iP and iliAD rats. This research component integrates well with the Center's theme of studying genetic determinants of alcohol ingestion. The proposed project interacts directly with the following cores: Administrative, Animal Production, Genomics and Molecular Biology, and Proteomics. This rat genetic component complements the 2 research components dealing with Human Genetics, and scientifically interacts with the Mouse Selective Breeding and Genetics Component. The results of this project will provide valuable information on mechanisms underlying alcohol addiction, which could lead to the development of pharmacotherapies for the treatment of alcoholism and alcohol abuse.